N-protonated and O-protonated tautomers of 1-azabicyclo[3.3.1]nonan-2-one: observation of individual 13 C-NMR carbonyl peaks and comparisons with protonated tautomers of planar and other distorted lactams Jessica Morgan a and Arthur Greenberg a * An earlier study fit calculated dynamic 13 C-NMR spectra in trifluoroacetic acid (TFA) (with added sulfuric acid) to slow exchange between N-protonated and O-protonated tautomers of 1-azabicyclo[3.3.1]nonan-2-one. The present study reports simultaneous observation of both carbonyl 13 C peaks in 40% sulfuric acid/60% TFA at 40  C. This furnishes the only example in which experimental carbonyl 13 C chemical shifts may be compared with a neutral lactam (in TFA or CDCl 3 ) with its N-protonated and O-protonated derivatives. The seemingly anomalous upfield chemical shifts (experimental and computational) of the 13 C carbonyl peaks in this N-protonated lactam (and other twisted N-protonated lactams) relative to the free bases are compared with data for unstrained protonated lactams and amides. The results are rationalized through conventional resonance structures. Copyright © 2012 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this paper Keywords: 1-azabicyclo[3.3.1]nonan-2-one; bridgehead bicyclic lactams; non-planar amides; 13 C-NMR carbonyl chemical shifts; N-protonation and O-protonation INTRODUCTION Protonation of an unstrained planar amide or lactam is heavily favored to occur on oxygen over nitrogen. For example, the calculated enthalpy difference (HF 6–31 G*//6–31 G* with ZPE and thermal corrections) for N-methylpyrrolidone favors O-protonation by 15 kcal/mol. [1,2] In marked contrast, for 1-azabicyclo[2.2.2]octan-2-one, which maintains an amide linkage with a 90-degree twist, the corresponding calculation favors N-protonation by 23 kcal/mol. [1,2] In accordance with Dunitz and Winkler, [3] there are three independent parameters that describe amide distortion. One of these, pyramidalization at the carbonyl carbon (w C ), is usually negligible (near 0  ). Distortion occurs principally through pyramidalization of nitrogen (w N ) and torsion about the N–CO bond (t). Given the nearly 40kcal/mol dichotomy earlier, what distortion parameters correspond to near-equivalence (‘ crossover’) of N-protonation and O-protonation of an amide linkage? The earlier computational study predicted that 1-azabicyclo[3.3.1]nonan-2-one (1, w N = ~50  ; t = ~20  ) favors N-protonation by less than 2 kcal/mol, [1,2] and thus, both the N-protonated (2) and O-protonated (3) tautomers could possibly be observed in equilibrium in strong acid. The computational prediction has been confirmed through NMR as well as UV spectroscopies. [4] A variable temperature 13 C-NMR study of the broadened carbonyl peak (182.5 ppm at ~25  C) displayed coalescence (complete disappearance of the peak) at ~0  C with reemergence of a very broad peak at 179 ppm at ~ 10  C that sharpened slightly at ~ 15  C. This peak was attributed to the N-protonated tautomer. The solvent employed, trifluoroacetic acid (TFA, mp 15  C), is not suited for lower temperature study and ‘freezing out’ of both carbonyl 13 C peaks was not observed. The density function theory DFT cal- culation of 13 C-NMR chemical shifts predicted a value ~15 ppm further downfield for the less abundant O-protonated tauto- mer. [4] A computed dynamic NMR comparison (employing 179 and 194 ppm and a 4:1 ratio of N-protonated versus O-protonated tautomers, respectively) provided a good fit to the limited experi- mental data. [4] In order to attempt to observe the carbonyl 13 C peaks for both tautomers, a different solvent system was employed in the present study: 40% sulfuric acid/60% TFA. An interesting observation is the counter-intuitive upfield shift of the carbonyl carbon upon N-protonation of twisted lactams reported in the earlier study [4] as well as by other researchers (see Table 1). [5–8] Confirmed separa- tion of the peaks for both N-protonated and O-protonated tauto- mers would also add to the very limited 13 C carbonyl chemical shift data set for protonated amides and lactams and contribute toward the understanding of these counter-intuitive chemical shifts. * Correspondence to: Arthur Greenberg, Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA. E-mail: Art.Greenberg@unh.edu a J. Morgan, A. Greenberg Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA Short Communication Received: 10 July 2012, Revised: 9 August 2012, Accepted: 15 August 2012, Published online in Wiley Online Library: (wileyonlinelibrary.com) DOI: 10.1002/poc.3030 J. Phys. Org. Chem. 2012 Copyright © 2012 John Wiley & Sons, Ltd.